Evaluation of Acute Nonlymphocytic Leukemia and Its Subtypes With Updated Benzene Exposure and Mortality Estimates: A Lifetable Analysis of the Pliofilm Cohort.

OBJECTIVE: US Environmental Protection Agency (EPA) based its benzene carcinogenicity assessment on the Pliofilm cohort. We evaluated associations between benzene exposure and acute nonlymphocytic leukemia (ANLL) and acute myelocytic leukemia (AML) risks using this cohort's updated exposure estimates and mortality data. METHODS: We calculated standardized mortality ratios (SMRs) for ANLL/AML using lifetable analyses, with various exposure quantile categories and lag times. RESULTS: Workers in the highest exposure categories had significantly elevated risks of ANLL and AML; no leukemia cases occurred in lower exposure categories. Exposure within 10 years of cancer onset appears most relevant for leukemia induction. CONCLUSIONS: Our results confirmed the association between high-level benzene exposures and leukemia risks, and provided further evidence of a threshold effect and relevant exposure window. Our findings call for an updated risk assessment for benzene carcinogenicity using updated exposure estimates and mortality data.

Evaluation of adverse human lung function effects in controlled ozone exposure studies.

The US EPA is evaluating controlled human ozone exposure studies to determine the adequacy of the current ozone National Ambient Air Quality Standard of 75 ppb. These studies have shown that ozone exposures of 80 ppb and greater are associated with lung function decrements. Here, we critically review studies with exposures below 80 ppb to determine the lowest ozone concentration at which decrements are causally associated with ozone exposure and could be considered adverse using the Adverse Effects/Causation Framework. Regarding causation, the framework includes consideration of whether exposure-related effects are primary or secondary, statistically significant, isolated or independent, or due to study limitations. Regarding adversity, the framework indicates one should consider whether effects are adaptive, compensatory, precursors to an apical effect, severe, transient and/or reversible. We found that, at exposures below 72 ppb ozone, lung function effects are primary effects, but are isolated, independent and not statistically different compared to effects observed during filtered air exposure, indicating a lack of causation. Up to 72 ppb, lung function effects may be precursors to an apical effect, but are not likely adverse because they are transient, reversible, of low severity, do not interfere with normal activity and do not result in permanent respiratory injury or progressive respiratory dysfunction. Overall, these studies do not demonstrate a causal association between ozone concentrations in the range of the current National Ambient Air Quality Standard and adverse effects on lung function.

A statistical reevaluation of the data used in the Lanphear et al. ( 2005 ) pooled-analysis that related low levels of blood lead to intellectual deficits in children.

A pooled-analysis by Lanphear et al. (2005) of seven cohort studies of the association between blood lead (BPb) concentrations in children and measures of their intelligence concluded that "environmental lead exposure in children who have maximal blood lead levels <7.5 µg/dL is associated with intellectual deficits." This study has played a prominent role in shaping the public understanding of the effects upon children's IQ of low BPb exposures (e.g., BPb ≤ 10 µg/dL). Here we present a reanalysis of the data used by Lanphear et al. to evaluate the robustness of their conclusions. Our analysis differed from that of Lanphear et al. primarily in how we controlled for non-lead variables (allowing a number of them to be site-specific), how we defined summary measures of BPb exposure, and in how we decided which BPb measures and transformations best modeled the data. We also reproduced the Lanphear et al. analysis. Although we found some small errors and questionable decisions by Lanphear et al. that, taken alone, could cause doubt in their conclusions, our reanalysis tended to support their conclusions. We concluded that there was statistical evidence that the exposure-response is non-linear over the full range of BPb evaluated in these studies, which implies that, for a given increase in blood lead, the associated IQ decrement is greater at lower BPb levels. However at BPb below 10 µg/dL, the exposure-response is adequately modeled as linear. We also found statistical evidence for an association with IQ among children who had maximal measured BPb levels ≤7 µg/dL, and concurrent BPb levels as low as ≤5 µg/dL.

Measurement error in environmental epidemiology and the shape of exposure-response curves.

Both classical and Berkson exposure measurement errors as encountered in environmental epidemiology data can result in biases in fitted exposure-response relationships that are large enough to affect the interpretation and use of the apparent exposure-response shapes in risk assessment applications. A variety of sources of potential measurement error exist in the process of estimating individual exposures to environmental contaminants, and the authors review the evaluation in the literature of the magnitudes and patterns of exposure measurement errors that prevail in actual practice. It is well known among statisticians that random errors in the values of independent variables (such as exposure in exposure-response curves) may tend to bias regression results. For increasing curves, this effect tends to flatten and apparently linearize what is in truth a steeper and perhaps more curvilinear or even threshold-bearing relationship. The degree of bias is tied to the magnitude of the measurement error in the independent variables. It has been shown that the degree of bias known to apply to actual studies is sufficient to produce a false linear result, and that although nonparametric smoothing and other error-mitigating techniques may assist in identifying a threshold, they do not guarantee detection of a threshold. The consequences of this could be great, as it could lead to a misallocation of resources towards regulations that do not offer any benefit to public health.

Meta-analysis of nitrogen dioxide exposure and airway hyper-responsiveness in asthmatics.

The effects of 0.1 to 0.6 ppm nitrogen dioxide (NO2) on airway hyper-responsiveness (AHR) to airway challenges in asthmatics have been evaluated in several controlled exposure studies. The authors conducted meta-analyses and meta-regressions of these studies using several effect measures for AHR: a change (in NO2 versus air) in (1) the provocative dose of a challenge agent necessary to cause a specified change in lung function (PD), (2) the change in FEV1 after an airway challenge, and (3) the fraction of subjects with increased AHR. Although several effect estimates from the meta-analyses are statistically significant, they are all so small that they are not likely to be clinically relevant. More importantly, there are no exposure-response associations for any effect estimates based on linear meta-regressions or analyses of effect estimates for exposure groups (0.1 to <0.2 ppm, 0.2 to <0.3 ppm, etc.). This is also generally the case for analyses stratified by airway challenge (specific/nonspecific), exposure method (mouthpiece/whole chamber), and activity during exposure (rest/exercise). The results of these analyses indicate that, to the extent the effects observed are associated with NO2 exposure, they are sufficiently small such that they do not provide evidence that NO2 has a significant adverse effect on AHR at concentrations up to 0.6 ppm.

Ultralow-jitter, 1550-nm mode-locked semiconductor laser synchronized to a visible optical frequency standard.

Using high-bandwidth feedback, we have synchronized the pulse train from a mode-locked semiconductor laser to an external optical atomic clock signal and achieved what is to our knowledge the lowest timing jitter to date (22 fs, integrated from 1 Hz to 100 MHz) for such devices. The performance is limited by the intrinsic noise of the phase detector used for timing-jitter measurement. We expect such a highly stable device to play an important role in fiber-network-based precise time/frequency distribution.